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    Shiga Toxin 2 Reduces Complement Inhibitor CD59 Expression on Human Renal Tubular Epithelial andGlomerular Endothelial Cells

    发布于：2013年7月29日    文字：【大】【中】【小】

    Infect Immun. 2013 Aug;81(8):2678-85. doi: 10.1128/IAI.01079-12. Epub 2013 May 20.

    Shiga Toxin 2 Reduces Complement Inhibitor CD59 Expression on Human Renal Tubular Epithelial andGlomerular Endothelial Cells.

    Ehrlenbach S, Rosales A, Posch W, Wilflingseder D, Hermann M, Brockmeyer J, Karch H, Satchell SC, Würzner R, Orth-H?ller D.

    Abstract: Infections with enterohemorrhagic Escherichia coli (EHEC) are a primary cause of hemolytic-uremic syndrome (HUS). Recently, Shiga toxin 2 (Stx2), the major virulence factor of EHEC, was reported to interact with complement, implying that the latter is involved in the pathogenesis of EHEC-induced HUS. The aim of the present study was to investigate the effect of Stx2 on the expression of membrane-bound complement regulators CD46, CD55, and CD59 on proximal tubular epithelial (HK-2) and glomerular endothelial (GEnC) cells derived from human kidney cells that are involved in HUS. Incubation with Stx2 did not influence the amount of CD46 or CD55 on the surface of HK-2 and GEnC cells, as determined by fluorescence-activated cell sorter analysis. In contrast, CD59 was significantly reduced by half on GEnC cells, but the reduction on HK-2 cells was less pronounced. With increasing amounts of Stx2, reduction of CD59 also reached significance in HK-2 cells. Enzyme-linked immunosorbent assay analyses showed that CD59 was not present in the supernatant of Stx2-treated cells, implying that CD59 reduction was not caused by cleavage from the cell surface. In fact, reverse transcription-quantitative PCR analyses showed downregulation of CD59 mRNA as the likely reason for CD59 cell surface reduction. In addition, a significant increase in terminal complement complex deposition on HK-2 cells was observed after treatment with Stx2, as a possible consequence of CD59 downregulation. In summary, Stx2 downregulates CD59 mRNA and protein levels on tubular epithelial and glomerular endothelial cells, and this downregulation likely contributes to complement activation and kidney destruction in EHEC-associated HUS。

    志贺毒素引起HUS（D+HUS）与毒素对肾脏内皮细胞的直接毒性及致凋亡作用密切相关，之后的研究逐渐发现补体活化在D+HUS中也发挥重要作用。补体活化机制推测为：志贺毒素可以直接干扰H因子作用；内皮细胞损伤后继发血栓形成，凝血过程可以活化补体；中心粒细胞和血小板活化后可激活补体。本文发现补体活化的另外一种机制。通过把志贺毒素2（Stx 2）与人肾小球内皮细胞和近端肾小管上皮细胞共孵育，结果发现：肾小球内皮细胞和近端肾小管上皮细胞表面的CD46（膜辅助因）和CD55（补体衰变加速因子）表达未减少，而CD59（可抑制膜攻击复合物的形成）在两者细胞细胞膜上的表达减少，上清液中CD59未增加；另外发现细胞内CD59 mRNA的表达减少，可能能解释细胞膜表面CD59的表达减少；在近端肾小管上皮细胞上发现补体活化终末产物沉积增加，可能与CD59的表达减少相关。

    结论：Stx2可以使肾小球内皮细胞和近端肾小管上皮细胞CD59 mRNA和细胞膜上的CD59表达减少，从而参与补体活化及D+HUS发病。

    http://www.ncbi.nlm.nih.gov/pubmed/23690395